DESCRIPTION Because of the central role of enzymes in all chemical processes in living systems, the mechanisms by which enzymes work have long been targets of extensive study. Understanding enzyme mechanisms provides a key to drug design, use of enzymes for synthesis, design of altered enzymes, and other such uses. Significant advances continue to be made in understanding the dynamics of enzymatic catalysis through the interaction of x-ray crystallography, site-directed mutagenesis, resonance spectroscopy and a variety of kinetic techniques. Among these, isotope effects are particularly suited for detailed studies of the nature and relative rates of chemical events within an enzyme active site and the minutiae of its catalytic action. Aspartate transcarbamylase is an ideal object for extensive study by means of isotope effects since (a) x-ray structures of several forms of the enzyme are available; (b) a variety of site-specific mutants have been isolated; (c) this enzyme is a model for allostericity with T and R states well characterized; (d) a wealth of isotope exchange data exists. Learning intimate details of mechanisms from the isotope effects on complex systems can be extremely enhanced by simultaneous use of modern quantum chemistry. Alternative pathways may be excluded based on the comparison between the observed experimental value of an isotope effect and values predicted for pathways indistinguishable by other methods. This can be achieved by using a few levels of theoretical scrutiny; semi-empirical, ab-initio, or DFT. Several isotope effects for the ATCase reaction available in the literature allow precise calibration of such calculations which should result in the ability to learn details of all steps of enzymatic catalysis and chemical steps for this enzyme.